The present invention relates to pharmaceutical drug delivery systems for the controlled release of active agents having a narrow absorption window in the gastrointestinal tract, i.e. are usually absorbed in the duodenum and/or jejunum. The invention also relates to the uses of these controlled release delivery systems in the treatment of gastrointestinal-associated disorders and diseases in mammals.
Pharmaceutical dosage forms which retain in the stomach for a prolonged period of time after oral administration, and release the active ingredient in a controlled manner are important for delivery of a wide variety of drugs. Various pharmaceutical controlled release drug delivery systems with prolonged gastric retention time have been described in the literature, which involve different technologies.
The advantages of using drug delivery systems are many. Of major importance in controlled drug therapy is the improved efficiency in treatment. Controlled drug therapy reduces the required frequency of administration, and single doses at periodic intervals are sufficient, resulting in improved patient compliance.
However, conventional controlled release drug delivery systems have only limited use for (1) drugs having a narrow absorption window in the gastrointestinal tract, i.e. are absorbed in the duodenum and/or jejunum; (2) local treatment of proximal parts of the gastrointestinal tract (stomach and/or duodenum); and (3) drugs which degrade in the colon. To enable the improved therapy in these cases, a gastroretentive pharmaceutical dosage form should be developed. After oral administration, such gastroretentive dosage form should retain in the stomach and release the drug in a controlled and prolonged manner. Examples of gastroretentive dosage forms are floating dosage forms and dosage forms that expand, swell or unfold in the stomach.
The rationale for developing expandable drug delivery systems is based on the nature of the pyloric antrum that, by means of antiperistaltic motion, retropels large bodies away from the pylorus back to the fundus and body of the stomach, thus prolonging their gastric retention time (GRT). Such dosage forms should preferably be designed to undergo biodegradation or disintegration, to enable their evacuation from the stomach.
U.S. Pat. No. 3,574,820 teaches the use of a gelatin matrix which hydrates in the stomach, gels, swells and cross-links with N-acetyl-homocysteine thiolactone to form a matrix too large to pass through the pylorus.
U.S. Pat. No. 4,207,890 discloses a drug dispensing device which comprises a collapsed, expandable imperforate envelope, made of a non-hydratable, body fluid and drug-permeable polymeric film, which contains the drug, and an expanding agent also contained within the polymeric envelope which, when in contact with body fluids, causes the envelope to expand to a volume such that the device is retained in the stomach.
U.S. Pat. No. 4,434,153 describes a device comprised of a matrix formed of a hydrogel that absorbs and imbibes fluid from the stomach, expands and swells, in order to retain in the stomach for an extended period of time, and a plurality of tiny pills dispersed throughout the matrix, having a drug-containing core and a fatty acid and wax wall surrounding the core
A significant disadvantage of the devices of the above publications is that they appear to ignore natural contractions of the stomach which may contribute to a rapid diminishing of size, leading to early removal of the device from the stomach. These devices lack the mechanical strength required to withstand the natural mechanical activity, that includes contractions of the stomach.
U.S. Pat. Nos. 4,767,627, 4,735,804 and 4,758,436 present dosage forms of various geometries: continuous solid stick; tetrahedron; planar disc; multi-lobed flat device; and ring. The devices are compressible to a size suitable for swallowing, and are self-expandable to a size which prevents passage through the pylorus. They are sufficiently resistant to forces of the stomach to prevent rapid passage through the pylorus for a pre-determined period of time and erode in the presence of gastric juices. The devices are homogenous, namely they contain the same polymer constitution in different areas of the device. The tetrahedron presented in U.S. Pat. No. 4,735,804 is homogenous in its four lobes, which are attached to each other by a polymeric matrix.
The medicaments are incorporated into the device as a liquid solution or suspension, which may necessitate the addition of mentioned preservatives or buffering agents. Alternatively, the controlled release drug module may be tethered or glued to the device.
U.S. Pat. Nos. 5,002,772 and 5,443,843 disclose an oral drug delivery system having a delayed gastrointestinal transit, which releases the drug/s contained therein in a controlled manner and which in their expanded form resist gastrointestinal transit. These delivery systems comprise one or more retention arms as a non-continuous compressible element, and an attached controlled release drug-containing device. The preferred configuration is a coil or a spiral. These systems must comprise at least two distinct parts (at least one retention arm and a controlled release device).
U.S. Pat. Nos. 5,047,464 and 5,217,712 describe a system comprising bio-erodible, thermoset, covalently cross-linked, poly(ortho) ester polymers, which expand from a compressed state upon delivery thereof. The acidic environment of the stomach eventually results in the degradation of the polymers within the system, thus permitting its removal from the stomach. The system is characterized by high resiliency.
Finally, U.S. Pat. No. 5,651,985 describes a system devised from a mixture of polyvinyl-lactams and polyacrylates which are characterized by their high degree of swelling in the stomach resulting in its retention in the stomach for a prolonged period of time.
Notwithstanding the developments in gastric retention devices, known devices still suffer many drawbacks, and there is need for yet improved delivery systems. The present invention is aimed at such improved devices, which would overcome the drawbacks of known devices.
It is therefore an object of the invention to provide a controlled-release drug delivery system that would retain in the stomach for a sufficient period of time, while releasing the active drug therefrom.
This and other objects of the invention would become clearer as the description proceeds.
The present invention relates to a pharmaceutical gastroretentive drug delivery system for the controlled release of an active agent in the gastrointestinal tract, which system comprises:
a) a single- or multi-layered matrix having a two- or three-dimensional geometric configuration comprising a polymer that does not retain in the stomach more than a conventional dosage form, said polymer selected from:
(1) a degradable polymer selected from:
(i) a hydrophilic polymer which is not instantly soluble in gastric fluids;
(ii) an enteric polymer substantially insoluble at pH less than 5.5;
(iii) a hydrophobic polymer; and
(iv) any mixture of at least two polymers as defined in (i), (ii) or (iii);
(2) a non-degradable; and
(3) a mixture of at least one polymer as defined in (1) with at least one polymer as defined in (2);
b) a continuous or non-continuous membrane, that does not retain in the stomach more than a conventional dosage form, affixed or attached to said matrix, said membrane comprising at least one polymer having a substantial mechanical strength; and
c) a drug, which may be in a particulate form or optionally contained within a drug-containing means; said drug or drug contained within said drug-containing means being embedded in a layer of said matrix, or being entrapped between at least two layers of said matrix, or being attached to said delivery system,
wherein said matrix when affixed or attached to said membrane prevents evacuation from the stomach of said delivery system for a period of time of from about 3 to about 24 hours.
The delivery system of the invention may further comprise a shielding layer covering at least one face of said matrix, optionally covering all or part of said membrane, said shielding layer comprising a polymer that does not retain in the stomach more than a conventional dosage form, said polymer being selected from (a) a hydrophilic polymer which is not instantly soluble in gastric fluids; (b) an enteric polymer substantially insoluble at pH less than 5.5; (c) a hydrophobic polymer; and (d) any mixture of at least two polymers as defined in any of (a), (b) or (c).
The drug contained in the delivery system of the invention may be in the form of raw powder, or a powder soluted, dispersed or embedded in a suitable liquid, semisolid, micro- or nanoparticles, micro- or nanospheres, tablet, capsule or a suitable specific two- or three-dimensional matrix.
The delivery system of the invention may further comprise a suitable plasticizer, which may be contained in any of the components of the delivery system. The plasticizer is preferably selected from the group consisting of an ester selected from phthalate esters, phosphate esters, citrate esters, fatty acid esters and tartarate esters, glycerine and glycol derivatives, and sorbitol. The plasticizer is preferably contained in the shielding layer.
In addition, the delivery system of the invention may further comprise at least one gas-forming agent. The gas-forming agent is preferably a liquid gas- forming agent which boils at body temperature or a solid gas-forming agent, preferably a pharmaceutically acceptable carbonate.
In a particular embodiment, the delivery system of the invention may additionally comprise an anti-adhering layer affixed to at least one outer face thereof. The anti-adhering layer preferably comprises a pharmaceutically acceptable cellulose or derivative thereof, silicate or an enteric polymer substantially insoluble at pH less than 5.5. In particularly preferred embodiments the said anti-adhering layer comprises microcrystalline cellulose.
The hydrophilic polymer comprised in the delivery system of the invention may be selected from the group consisting of a protein, a polysaccharide, a polyacrylate, a hydrogel, polyvinyl alcohol, polyvinyl pyrrolidone, and derivatives of such polymers.
The enteric polymer comprised in the delivery system of the invention may be selected from the group consisting of shellac, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and methylmethacrylate-methacrylic acid copolymers, preferably having a ratio of ester to free carboxylic groups of 2:1.
In a preferred embodiment, the delivery system of the invention comprises a shielding layer which comprises a mixture of said hydrophilic polymer and said enteric polymer and optionally further comprises s plasticizer. In such embodiments, the said hydrophilic polymer is preferably cross-linked with a suitable cross-linking agent particularly with glutaraldehyde. The hydrophilic polymer is preferably an enzymatically hydrolyzed cross-linked gelatin or a derivative thereof. The said enteric polymer is preferably methylmethacrylate-methacrylic acid copolymer having a ratio of ester to free carboxylic groups of 2:1. A particularly preferred plasticizer is glycerine.
In further specific embodiments, the hydrophobic non-degradable polymer comprised in the delivery system of the invention is selected from the group consisting of ethylcellulose, a copolymer of acrylic acid and methacrylic acid esters, having from about 5 to 10% functional quaternary ammonium groups, polyethylene, polyamide, polyvinylchloride, polyvinyl acetate and any mixtures thereof.
In yet a further particular embodiment, the membrane of the delivery system of the invention comprises hydrophobic non-degradable polymer/s, hydrophobic degradable polymer/s, or mixtures thereof. Preferably, the said membrane is comprised of a mixture of 1-poly(lactic acid) (1-PLA) and ethylcellulose at a ratio of 9:1, respectively.
The delivery system of the invention is suitable for the delivery of drugs having a narrow absorption window in the gastrointestinal tract. Such drugs may be therapeutic nucleic acids or amino acid sequences, nucleic acids or amino acid derivatives, peptidomimetic drugs, antibiotics, therapeutic ions, vitamins, bronchodilators, anti-gout agents, an anti-hypertensive agents, diuretic agents, anti-hyperlipidemic agents or ACE inhibitors.
The delivery system may also be particularly suitable for the delivery of drugs intended for local treatment of the gastrointestinal tract. Such drug may be anti-tumor agents, histamine (H2) blockers, bismuth salts, synthetic prostaglandins or antibiotic agents.
In addition, the delivery system of the invention may be suitable for the delivery of drugs that degrade in the colon, for example metoprolol.
The delivery system of the invention is particularly useful for the treatment of gastrointestinal associated disorders selected from peptic ulcer, nonulcer dyspepsia, Zollinger-Ellison syndrome, gastritis, duodenitis and the associated ulcerative lesions, stomach or duodenum neoplasms.
The delivery system of the invention may have the form of a disc, multi-lobed configuration, a triangle or a quadrangle, and may be planar or non-planar.
Further, the delivery system of the invention may be folded into a suitable capsule. Thus, in a further embodiment the invention also relates to a capsule containing a delivery system of the invention.